High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome

The application of fluorescence in situ hybridization (FISH) using whole-ch romosome paints (WCPs) is proving to be a very powerful technique for revea ling chromosomal instability that, for the most part, has gone undetected b y conventional cytogenetic analysis. We have analyzed the frequency of tran slocations in lymphocytes and lymphoblastoid cell lines from ataxia telangi ectasia (AT) and Nijmegen breakage syndrome (NBS) homozygotes and heterozyg otes using a three-color chromosome-painting technique (WCP 1, 2, 4). With this assay we were able to detect an increased frequency of spontaneous tra nslocations in AT homozygotes (median, 18.47 +/- 10.82 translocations per 1 ,000 metaphase cells: 10 patients) and AT heterozygotes (median, 7.87 +/- 3 .15 translocations per 1.000 cells, 7 patients), in comparison to controls (median. 2.26 +/- 1.75 translocations per 1,000 cells; 10 controls). Analys is of NBS homozygotes(median. 19.05 +/- 11.27 translocations per 1.000 cell s, 5 patients) and NBS heterozygotes (median, 6.93 +/- 3.04 translocations per 1,000 cells; 6 patients) also showed an increased frequency of transloc ations in these patients compared to controls. The presence of such hithert o undetected chromosomal aberrations corroborate previous findings of spont aneous chromosomal instability in AT and NBS patients, as manifested by an increased rate of open breaks and rearrangements involving chromosomes 7 an d 14. Moreover, we show that the degree of genomic instability in AT and NB S patients is even higher than previously established and that some AT and NBS heterozygotes evidence spontaneous chromosomal instability as well. The se increased levels of nonspecific translocations could be an important ris k factor for the development of malignancies in homozygotes and heterozygot es for ATM or NBS 1 gene mutations. Copyright (C) 2001 S. Karger AG, Basel.